Structural elucidation of degradation products of a benzopyridooxathiazepine under stress conditions using electrospray orbitrap mass spectrometry - Study of degradation kinetic

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• 作者：Marie Lecoeur ; ^{marie.lecoeur@univ-lille2.fr} ; Valé ; rie Vé ; rones ; Claude Vaccher ; Jean-Paul Bonte ; Nicolas Lebegue ; Jean-Franç ; ois Goossens
• 关键词：Degradation kinetic ; Electrospray orbitrap mass spectrometry ; Fragmentation ; Liquid chromatography ; Validation
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2012
• 期刊代码：15_09280987
• 类别：pha
• 出版时间：11 April, 2012
• 卷：45
• 期：5
• 页码：559-569
• 文件大小：595 K

摘要

1-(4-Methoxyphenylethyl)-11H-benzo[f]-1,2-dihydro-pyrido[3,2,c][1,2,5]oxathiazepine 5,5 dioxide (BZN) is a cytotoxic derivative with very promising in vitro activity. Regulatory authority for registration of pharmaceuticals for human use requires to evaluate the stability of active compound under various stress conditions. Forced degradation of BZN was investigated under hydrolytic (0.1 M NaOH, 0.1 M HCl, neutral), oxidative (3.3%H₂O₂), photolytic (visible light) and thermal (25 掳C, 70 掳C) settings. Relevant degradation took place under thermal acidic (0.1 M HCl, 70 掳C) and oxidative (3.3%H₂O₂) conditions. Liquid chromatography-mass spectrometry (LC-MS) analyses revealed the presence of ten degradation products whose structures were characterized by electrospray ionization-orbitrap mass spectrometry. The full scan accurate mass analysis of degradation products was confirmed or refuted using three tools furnished by the MS software: (1) predictive chemical formula and corresponding mass error; (2) double bond equivalent (DBE) calculation; and (3) accurate mass product ion spectra of degradation products. The structural elucidation showed that the tricycle moiety was unstable under thermal acidic and oxidative conditions since four degradation products possess an opened oxathiazepine ring. Then, a simple and fast HPLC-UV method was developed and validated for the determination of the degradation kinetic of BZN under acidic and oxidative conditions. The method was linear in the 5-100 渭g mL^鈭? concentration range with a good precision (RSD = 2.2%and 2.7%for the repeatability and the intermediate precision, respectively) and a bias which never exceeded 1.6%, whatever the quality control level. With regards to the BZN concentration, a first-order degradation process was determined, with t_1/2 = 703 h and 1140 h, under oxidative and acidic conditions, respectively.